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Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.

Original publication

DOI

10.1038/ng879

Type

Journal article

Journal

Nat Genet

Publication Date

05/2002

Volume

31

Pages

55 - 59

Keywords

Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Female, Genes, BRCA1, Genes, BRCA2, Genetic Testing, Heterozygote, Humans, Male, Microsatellite Repeats, Mutation, Pedigree, Protein Kinases, Protein-Serine-Threonine Kinases, Risk Factors, Sequence Deletion